ABSTRACT Nonmelanoma skin cancer is the most common cancer in the USA, occurring in 1 of 5 Americans during their lifetime. The incidence of skin cancer is rising as well, due to increased exposure to sunlight and other sources of ultraviolet (UV) irradiation, the primary cause of approximately 90% of skin cancers. Excessive UV radiation exposure to the skin results in oxidative stress that can overwhelm the natural antioxidant defenses of the skin. This leads to significant and rapid generation of reactive oxygen species (ROS). ROS can cause DNA damage and lead to mutations and cancer. Currently used sunscreens and antioxidants are not adequate to prevent or protect against UV exposure. Sunscreens are particularly poor at blocking the long wavelength UVA that produces much of the ROS and must be frequently reapplied, while antioxidants typically used to protect skin have poor stability and do not penetrate the skin to reach the basal epidermal keratinocytes at risk for oncogenic transformation. Therefore, we reasoned that effective and sustained delivery of antioxidants, particularly superoxide dismutase (SOD) and catalase (CAT), to the skin could prevent oxidative stress- induced oncogenic responses and hence skin cancer. To investigate this hypothesis, we will utilize a novel agent, Pro-NP?, which consists of a biodegradable nanoparticle shell containing the antioxidant enzymes SOD and CAT. Pro-NP? is formulated using an FDA approved biodegradable and biocompatible polymer that protects the encapsulated enzymes from degradation and allows their release in active form over a sustained period of time. Our preliminary data in human epidermal tissue equivalents show that Pro-NP? penetrates to the deepest layers of the epidermis and prevents UV-induced increases in ROS and DNA damage. We hypothesize that topical application of Pro-NP? will safely deliver SOD and CAT to the basal keratinocytes of the skin to prevent ROS generation in response to UV irradiation, and thus reduce DNA damage and skin cancer development. This hypothesis will be tested using UV exposure of Hairless SKH1 mice to 1) evaluate the effectiveness of Pro-NP? for delivering antioxidant enzymes into the skin for prevention of UV- induced ROS, reactive nitrogen species, and DNA damage and 2) assess the safety and efficacy of Pro- NP? for prevention of UV-induced skin cancer. We anticipate successful proof-of-principle evidence of the ability of topical Pro-NP? treatment to safely prevent skin cancer in chronically UV irradiated skin.